Pain signals enter the nervous system in the spinal cord, where these signals are processed before being transmitted to the brain. This grant seeks to understand how that processing goes awry after injury, leading to constant pain without stimulation and burning pain when the skin is lightly touched. The ultimate goals are to identify better ways to treat chronic pain and also to prevent it at the time of injury. Chronic pain occurs after physical trauma, whether on the battlefield, in civilian life, or from major surgery. Treatment and prevention of chronic pain remains difficult, and the proposed work addresses the mission of NIGMS and the NIH to understand and better treat disorders of the central nervous system, including pain. Childbirth, which also causes physical trauma, particularly by cesarean delivery, only rarely causes chronic pain, suggesting a protective mechanism during this period. Rodents also fail to develop chronic pain after surgery if it is performed at the time of delivery, and preliminary studies suggest this is due to release of the hormone, oxytocin, into the spinal cord by nerves which descend from the hypothalamus. To determine the mechanisms for this important protection against chronic pain from physical trauma, this grant will perform 3 types of studies. The first set of studies will use specific treatments in rats which either prevent the oxytocin nerves in the hypothalamus from being stimulated at the time of delivery or to prevent the action of oxytocin itself in the spinal cord to better understand the role of this descending oxytocin pathway in protection against pain and neurochemical changes which occur in the spinal cord when chronic pain from physical trauma develops. To do this surgery will be performed in rats and their behavior measured, and proteins and cell structure in their spinal cord tissue will be examined. The second set of studies will test whether the delivery period and oxytocin in the spinal cord protect against chronic pain by changing the activity of sensory nerves coming from the skin. To do this recordings from sensory nerves will be made in anesthetized animals to first understand whether pain from light touch after injury is due to an abnormal signal from them. Then the effect of delivery and oxytocin will be determined on these sensory nerves. The third set of studies will test in new mothers whether the burning and hypersensitive response on the skin from application of capsaicin cream, a model of temporary pain sensitivity, are reduced compared to women without children. We will also, under FDA oversight, test the safety of injecting oxytocin into the spinal space of men and women and determine whether it reduces pain and hypersensitivity in experimental conditions in normal volunteers and in those with chronic low back pain. PUBLIC HEALTH RELEVANCE: If we are to prevent chronic pain from developing after war or civilian injuries we need to better understand the process by which it occurs and conditions which protect against it. This grant explores the clinical observation that trauma during childbirth very rarely causes chronic pain in order to understand this protection and apply it to other settings. The results may improve our treatment of chronic pain and offer a new approach to prevent chronic pain occurring after physical trauma.